Glycerol-3-Phosphate Dehydrogenase

Glycerol-3-phosphate dehydrogenase (GlpD) is a membrane bound enzyme in prokaryotes and in eukaryotes. Glycerol 3-Phosphate Dehydrogenase (GlpD) is an oxidoreductase enzyme which catalyzes the reduction in of Dihydroxyacetone Phosphate to Glycerol 3-Phosphate, with NADH as the reductant. GlpD is involved in many cellular functions such as phospholipids biosynthesis, respiration and metabolism. The GlpD is a dimer consisting of two subunits which contain the catabolite activator protein (CAP)-Domain,the flavin adenine dinucleotide(FAD)-Domain and a ubiquinone analogue, MD.

Structure


GlpD is a dimer that consists of two subunits; α and β. The GlpD structure also contains seven ligands; 1,3-Dihydroxyacetonephosphate (13P), β-Octylglucoside (βOG), 1,2-Ethanediol (EDO), Flavin-Adenine Dinucleotide (FAD), Imidazole (IMD), PO4 (Phosphate Ion) and N-(Tris(Hydroxymethyl)methyl)-3-Aminopropanesulfonic Acid (T3A). The active sites on GlpD are the Cap-Domain, FAD- Domain and a ubiquinone substrate analogue, menadione (MD).

Cap-Binding Domain

The C-terminal CAP-Domain consists of negatively charged residues that are opposite in orientation to the positively charged residues of the FAD-Domain in the phospholipid membrane. The CAP-domain is responsible in gene transcription and helical turns.

FAD Active Site

The N-terminal FAD-Domain exists in each monomer subunit of GlpD and is embedded into the phospholipid membrane bilayer.Substrate binding occurs at this domain which causes a conformational change to the structure of the GlpD enzyme. The FAD-domain plays a major role in metabolism and energy synthesis.

Function
GlpD functions in the intracellular membrane of E. coli and in the inner-mitochondrial membrane of eukaryotes. In E. Coli, GlpD catalyzes and reduces the reaction of dihydroxyacetone phosphate to glycerol 3-phosphate in the glycerol metabolism pathway. The binding of the substrate analogues (glyceraldehydes 3-phosphate, glyceric acid 2-phosphate and phosphoenolpyruvate, dihydroxyacetone phosphate)or UQ substrate analogues (2-n-heptyl-4-hydroxyquinoline N-oxide and menadione). The conformational change of the structure and resiudes of GlpD catalyzes many different metabolic reactions.

Phosphoplipid Biosynthesis
GlpD reduces dihydroxyacetone phosphate to glycerol 3-phosphate. Then the glycerol 3-phosphate is catalyzed by acyl transferase to 1-acylglyverol-3-phosphate, and then another acyl transferase catalyzes that to a phosphatidic acid. head groups are added to the phosphatidic acid to synthesize phospholipids.

Glyceroneogenesis
GlpD is also involved in the glyceroneogenesis pathway. By gluconeogenesis, phosphoenolpyruvate converts to dihydroxyacetone phosphate which is reduced by GlpD to glycerol 3-phosphate which then forms a backbone for the synthesis of triacylglycerol.

Respiration
The FAD-domain in GlpD plays a major role in the transport of electrons into the repiratory pathway. Glycerol 3-phosphate is oxidized to dihydroxyacetone phosphate with simultaneous reduction of of FAD to FADH2 occuring, and the electrons are transported to Ubiquinone, which are further transported to oxygen or nitrogen and into the respiratory pathway.

Diseases
GlpD is involved in diseases such as alzeheimer`s, muscle dystrophy, hyaline membrane diseases and many more.

3D structures of glycerol-3-phosphate dehydrogenase
3da1 – GPDH + FAD – Bacillus halodurans

2qcu - EcGPDH + FAD – Escherichia coli

2r4j, 2r4e - EcGPDH + FAD + DHAP

2r46 - EcGPDH + FAD + 2-phosphopyruvic acid

2r45 - EcGPDH + FAD + 2-phospho-glyceric acid

1yj8 – GPDH – Plasmodium falciparum

NADPH-dependent GPDH
3k96 – GPDH – Coxiella burnetii

2pla, 1x0x – hGPDH + NAD – human

1wpq - hGPDH + NAD + DHA

1x0v – hGPDH

1z82 – GPDH + NADP + G3P + glyceraldehydes-3-phosphate – Thermotoga maritima

1txg – GPDH + glycerol – Archaeoglobus fulgidus

1evy – GPDH – Leishmania mexicana

1n1g, 1m66, 1m67, 1jdj – LmGPDH + inhibitor

1evz - LmGPDH + NAD

1n1e – LmGPDH + NAD + DHAP